the influence of 6 months of oral anabolic steroids on body mass and respiratory muscles in...

DOI 10.1378/chest.114.1.19 1998;114;19-28Chest

Goldstein, Noe Zamel, Dina Brooks and Jose R. JardimIvone Martins Ferreira, Ieda T. Verreschi, Luiz E. Nery, Roger S. COPD PatientsRespiratory Muscles in UndernourishedAnabolic Steroids on Body Mass and The Influence of 6 Months of Oral

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The Influence of 6 Months of Oral Anabolic Steroidson Body Mass and Respiratory Muscles inUndernourished COPD Patients*Ivone Martins Ferreira, MD, PhD; leda T. Verreschi, MD, PhD;Luiz E. Nery, MD, PhD; Roger S. Goldstein, MD, FCCP;Noe Zamel, MD, FCCP; Dina Brooks, BSc (PT), PhD; andJose R. Jardim, MD, PhD

Study objective: To evaluate the influence of oral anabolic steroids on body mass index (BMI),lean body mass, anthropometric measures, respiratory muscle strength, and functional exercisecapacity among subjects with COPD.Design: Prospective, randomized, controlled, double-blind study.Setting: Pulmonary rehabilitation program.Participants: Twenty-three undernourished male COPD patients in whom BMI was below 20kg/m2 and the maximal inspiratory pressure (PImax) was below 60% of the predicted value.Intervention: The study group received 250 mg of testosterone IM at baseline and 12 mg of oralstanozolol a day for 27 weeks, during which time the control group received placebo. Both groupsparticipated in inspiratory muscle exercises during weeks 9 to 27 and cycle ergometer exercisesduring weeks 18 to 27.Measurements and results: Seventeen of 23 subjects completed the study. Weight increased innine of 10 subjects who received anabolic steroids (mean, +1.8±0.5 kg; p<0.05), whereas thecontrol group lost weight (.0.4±0.2 kg). The study group's increase in BMI differed significantlyfrom that of the control group from weeks 3 to 27 (p<0.05). Lean body mass increased in thestudy group at weeks 9 and 18 (p<0.05). Arm muscle circumference and thigh circumference alsodiffered between groups (p<0.05). Changes in PImax (study group, 41%; control group, 20%)were not statistically significant. No changes in the 6-min walk distance or in maximal exercisecapacity were identified in either group.Conclusion: The administration of oral anabolic steroids for 27 weeks to malnourished malesubjects with COPD was free of clinical or biochemical side effects. It was associated withincreases in BMI, lean body mass, and anthropometric measures ofarm and thigh circumference,with no significant changes in endurance exercise capacity. (CHEST 1998; 114:19-28)

Key words: anabolic steroids; body mass index; chronic obstructive pulmonary disease; nutrition; respiratory musclefunction

Abbreviations: BMI=body mass index; DEXA=dual energy x-ray absortiometry; IMT=inspiratory muscletraining; LH=luteinizing hormone; PEmax=maximal expiratory pressure; PImax=maximal inspiratory pressure;Vo2max=maximal oxygen consumption

\M alnutrition is associated with severe COPD,*.**- having been observed in 10 to 26% of outpa¬tients with COPD and in up to 47% of patients*From the Respiratory Division of Federal University of SaoPaulo, Brazil (Drs. Ferreira, Nery, and Jardim); EndocrinologyDivision of Federal University of Sao Paulo, Brazil (Dr. Verre¬schi); and Division of Respiratory Medicine, University ofToronto, Canada (Drs. Goldstein, Brooks, and Zamel).Manuscript received June 25, 1997; revision accepted February11, 1998.Supported by Fundacao de Amparo a Pesquisa de Sao Paulo(FAPESP) and Conselho National de Pesquisa do Brazil (CNPq).Reprint requests: Ivone Martins Ferreira, MD, c/o Roger S.Goldstein, MD, West Park Hospital, 82 Buttonwood Ave,Toronto, Ontario M6M 2J5, Canada

hospitalized with acute respiratory failure.1 Althoughthe underlying mechanisms and pathophysiology re¬

main unclear, at least one report has noted thatindividuals who lost weight had a higher morbidityand mortality compared with those whose weightwas within predicted values for their age, height, andsex.2 When compared with normal-weight patientswith similar airflow limitation, low-weight COPDpatients had more hyperinflation, more gas trapping,a lower diffusing capacity,3 more dyspnea, and re¬

duced exercise capacity.4Malnutrition affects the composition5 and the

function6 of the respiratory muscles. As in other

CHEST/114/1 /JULY, 1998 19



skeletal muscles, protein is degraded to produceenergy and to assist with the synthesis of visceralprotein. In subjects with COPD whose weight was

reduced to 70% of predicted values, diaphragmaticmass was reduced to 60%. Reductions in the thick¬ness of the sternocleidomastoid muscles also havebeen reported.7 This reduction in respiratory musclemass reduces the capacity of the ventilatory systemto respond to the increases in elastic and resistiveloads, such as those present during exercise or withrespiratory exacerbations.Over the past 20 years, a variety of reports have

claimed that anabolic steroids improved the perfor¬mance of high-level athletes consequent to improve¬ments in skeletal muscle mass and strength.8-11Although in some individuals the gains in musclestrength associated with good nutrition and exercise

appear to be further enhanced by the addition ofanabolic androgenic steroids, errors in design, anal¬ysis, and reporting have limited the credibility ofmany studies. A recent meta-analysis on the effectsof anabolic steroids in healthy volunteers concludedthat there were slight improvements in strengthamong previously trained athletes. However, theauthors were unable to reach a conclusion regardingthe influence of anabolic steroids on overall athleticperformance.12

In a well-designed, randomized, controlled trial,testosterone combined with strength training was

found to increase fat-free mass as well as muscle sizeand strength among healthy male volunteers.13 Theauthors suggested that by extension, androgens maybe beneficial when administered for a limited periodin those with cachexia associated with chronic con¬

ditions. Schols and colleagues14 reported that sub¬jects with COPD sustained greater improvements infat-free muscle mass and in maximal inspiratorypressure (PImax) when anabolic steroids were addedto nutritional supplementation than when they re¬

ceived only nutritional support. The subjects were

given anabolic steroids IM at baseline and at 2, 4,and 6 weeks, and their primary outcomes (bodycomposition and respiratory muscle function) were

measured after 8 weeks.We were interested in learning whether oral ana¬

bolic steroids improve respiratory muscle functionand exercise capacity if administered over a more

protracted period of 6 months. Therefore, we under¬took a randomized, controlled trial in which an

anabolic steroid (stanozolol) was administered orallyfor 27 weeks to ambulatory undernourished individ¬uals with COPD. During the period of steroidadministration, study subjects participated in respi¬ratory rehabilitation, including cycle ergometry andinspiratory muscle training. Our primary outcome

measures were body mass index (BMI), muscle mass,respiratoiy muscle strength, and functional exercisecapacity.

Materials and Methods

PopulationTwenty-three ambulatory7 male patients with stable COPD (no

respiratory exacerbation for at least 6 weeks) were selected forthe study. Inclusion criteria included a BMI below 20 kg/m2 anda PImax below 60% of the predicted value. Subjects did not haveany other associated medical conditions that might have influ¬enced their weight or respiratory muscle function. Patients withprostate or known cardiac disease were excluded because of thepotential side effects of anabolic steroid administration. Theprotocol was approved by the Human Ethics Committee of theFederal University of Sao Paulo.

Protocol

After their informed consent was obtained, the subjects were

randomized in a double-blind fashion to receive either placebo(control group) or anabolic steroids (study group). Patients in theanabolic steroid group received 250 mg of testosterone IM(Durateston, a preparation containing phenpropionate, isocap-roate, propionate, and caproate of testosterone) at baseline as an

"attack" dose; the study group also took oral stanozolol (12mg/day) for 27 weeks.The study was divided into three 9-week periods. For the first

9 weeks, the study group received stanozolol and the controlgroup a placebo. Between weeks 9 and 18, both groups receiveddaily inspiratory muscle training (IMT) in addition to stanozololor placebo. During weeks 18 to 27, exercise training at approxi¬mately 80% of maximal work, as determined by a symptom-limited incremental exercise test, was added to this regimen. Acycle ergometer was used for training (Model II; Funbec; SaoPaulo, Brazil). This was calibrated regularly (physically andelectronically) by the manufacturer.Between weeks 9 and 27, IMT was performed for 20 min,

twice a day, at 20 breaths/min using a pressure-loaded device(Resp-Trein; Imebras; Sao Paulo, Brazil). Training was targetedto be at a pressure equal to 50% of PImax. PImax was measuredever)7 3 weeks using an analogue pressure gauge, and the targetpressure was adjusted as necessary. Although most of the IMTsessions were unsupervised, to promote subject compliancepatients had one session of supervised IMT every 3 weeks.During these sessions, subjects were provided with feedback on

their technique as well as encouragement. Family members were

encouraged to assist the subjects with their home rehabilitationprogram.Between weeks 18 and 27, patients performed cycle training at

the hospital for 30 min three times a week, at a workload equalto 80% of the maximal workload derived from the incrementalexercise test; sessions were supervised by a physical therapist. Ifthe patient was unable to perform at that workload, he startedwith a lower load and increased the load after 1 week. Onesubject who could not reach this workload trained at the maximallevel that he could achieve.

Measurements

At baseline and at 9-week intervals (9, 18, and 27 weeks), dualenergy x-ray absortiometry (DEXA) was performed to determine

20 Clinical Investigations



body composition (total lean body mass and percentage of fatmass). Tests of respirator)' muscle strength and endurance, the6~min walk test, and the incremental exercise test also were

performed at each of those times. Anthropometric measures andrespiratory muscle strength (PImax and maximal expiratory pres¬sure [PEmax]) were measured every 3 weeks.

Nutritional Assessment

Weight was measured in the morning using a beam scale, withthe patient clothed but not wearing shoes. Ideal body weight wasdetermined from the patient's weight range and frame size basedon the tables from Metropolitan Life Insurance.15BMI was calculated by dividing the patient's weight in kg by his

height squared (m2). We considered subjects with a BMI of lessthan 20 kg/nr to be undernourished.16To measure midarm circumference, the nondominant arm was

positioned parallel to the trunk and a nondistensible tape was

placed around the midpoint of the arm without compressing thearm tissue, halfway between the tip of the shoulder (acromialprocess) and the tip of the elbow (olecranon process). Threeconsecutive measurements were made. If there was agreementbetween them (within 0.5 cm), the intermediate measurementwas accepted as the actual value.

Triceps skinfold thickness was used as an indirect estimate ofbody fat. It was derived by gathering skin at the midarm pointbetween the thumb and the index finger and measuring itsthickness with a skinfold caliper. Three consecutive measure¬

ments were made. If there was agreement between them (within4 mm), the intermediate measurement was accepted as the actualvalue.The arm muscle circumference index reflects the amount of

muscle or lean tissue in the body. This measurement was derivedfrom the following equation: arm muscle circumference=midarm circumference.(3.14Xtriceps skinfold thickness).17With the patient standing and his weight evenly distributed,

the thigh circumference was determined on the nondominantside at half the distance between the inguinal crease and a pointmidway along the patella. Three consecutive measurements were

made. If there was agreement between them (within 0.5 cm), theintermediate measurement was accepted as the actual value.

Total body and soft-tissue composition were measured withdual energy X-ray absortiometry (DEXA). DEXA measurementswere made with a total body scanner (Model DPX; LunarRadiation Corp; Madison, Wise).

Total serum protein and albumin were obtained from venous

blood at baseline and every 9 weeks.

Respiratory Muscle Assessment

Respiratory muscle strength was assessed by measuring PImaxand PEmax (PImax at residual volume and PEmax at total lungcapacity) with an analogue pressure gauge using standard meth¬odology.18 Patients were seated and asked to make maximalefforts against an obstructed mouthpiece that had a small leak to

prevent patients from closing their glottis during the respiratorymaneuver. Patients had to sustain maximal effort for 1 s. The bestof five consecutive attempts was used, provided the variabilitybetween the best two efforts did not exceed 5%.19To measure respiratory muscle endurance, subjects breathed

through a pressure-dependent inspiratory device set to generatemouth pressures close to 80% of their PImax until they could no

longer maintain this pressure target. Endurance time and breath¬ing frequency were recorded. After the subjects practiced athome daily for a week, the baseline endurance was measured. Asan approximate measurement of the total work, we calculated the

product of pressure, inspiratory time, and number of breathsduring the endurance run. Inspiratory time was considered to be50% of total respiratory7 time.20

Exercise CapacityMaximal exercise capacity was assessed with a graded, symp¬

tom-limited exercise test. The test was performed using the CPXDiagnostic System (Medical Graphics Corp; St. Paul, Minn)linked to a cycle ergometer (CPE 2000; Medical Graphics Corp)with 10-W increments each minute. Maximal oxygen consump¬tion (Vo2max) was calculated as a percentage of the predictedvalue.Three 6-min walk tests were performed. During the first two

tests, patients were encouraged every 2 min. In the third test,they were encouraged and accompanied in order to achieve thebest performance.21 The value used was the greatest distance a

patient walked in 6 min in any of the three tests.

Side EffectsWe measured several indices that might reflect toxic effects of

anabolic steroids. Venous blood concentrations of testosteroneand luteinizing hormone (LH) were measured at baseline and at9,18, and 27 weeks. Screening for possible side effects associatedwith anabolic steroids was carried out according to World HealthOrganization guidelines.22 Liver function was assessed by mea¬

suring levels of serum aspartate aminotransferase, alanine ami-notransferase, gamma-glutamyltransferase, total bilirubin, conju¬gated bilirubin, and alkaline phosphatase. Every 9 weeks, we

recorded the international normalized ratio, partial thromboplas-tin time, fibrinogen level, platelet count, and platelet aggregationto monitor coagulation. Evaluation also included a completeblood count and measurement of prostatic acid phosphatase,triglycerides, total cholesterol, and lipoproteins. In addition, weperformed transrectal clinical evaluation of the prostate andtransrectal prostatic ultrasound. We also monitored cardiac func¬tion by means of ECGs, chest radiographs, and two-dimensionalechocardiograms.

Other Measures

Calcium, phosphorus, magnesium, sodium, potassium, andglucose levels were measured at baseline and at 9, 18, and 27weeks.

Statistical AnalysisData are presented as mean±SE. Nonparametric analysis of

variance was used to determine the significance of differencesbetween the two groups (Mann-Whitney) and between periods(Friedman). Results were considered statistically significant at

p<0.05.

RESULTS

The baseline features of the patients are shown inTable 1. There were no significant differences be¬tween groups at baseline. Both groups had a mean

BMI of 17.3 (below predicted values for their ageand sex), severe or moderate airway obstruc¬tion,23'2425 and reduced respiratory muscle strength.Data from six patients were excluded from analysis:

CHEST/114/1 /JULY, 1998 21 1998 by the American College of Chest Physicians

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Table 1.Anthropometric and Pulmonary FunctionData at Baseline*

Control Group(n=7)

Study Group(n=10)

Age, yrWeight, kgBMI, kg/m2% of ideal weightFEVX, % predFEV^FVC, %PImax, .cm H20PEmax, cm H£0Pa02, mm HgPaC02, mm Hg

66.1 (2.6)45.8(2.1)17.3 (0.6)79.1 (3.1)49.4 (5.9)41.6 (3.0)47.7 (3.7)114.0(8.8)66.0 (3.7)42.0 (2.9)

70.3 (1.5)46.1 (14.7)17.3 (0.5)78.4 (2.3)41.2 (4.5)39.7(2.7)43.2 (3.1)

113.4(8.1)71.2 (3.0)40.5(1.3)

*Data presented as mean (SEM). There were no significant differ¬ences between the control and study groups.

two patients in the control group died of respiratoryfailure before the study's end; one patient in eachgroup was unable to attend regularly for exercisemeasures; one member of the study group developedatelectasis associated with a non-small cell lungcancer; and one study patient was withdrawn be¬cause of depression. Thus, 17 patients completed theprotocol, 10 in the study group and seven in thecontrol group.There were numerous respiratory exacerbations,

including flulike illnesses (two control and five studysubjects), tracheobronchitis (12 control and 11 studysubjects), and pneumonia (one subject in each

group). All subjects with tracheobronchitis receivedantibiotics. Corticosteroids were administered for 5to 7 days in 11 subjects (five control and six studysubjects). During exacerbations, subjects missed 1week of exercise. They then restarted at a lowerworkload, gradually returning to their previous levelover 1 week. Measures of exercise tolerance were

postponed for 1 week and measures of respiratorymuscle strength and endurance were postponed for2 weeks. One control subject and two patients fromthe treatment group missed the last test because ofrespiratory exacerbations; their data for that test wasexcluded from analysis.The changes in anthropometric measurements in

study and control subjects during the 27-week periodare summarized in Figure 1. For changes in BMI,differences between groups were statistically signif¬icant at 3 weeks and were sustained throughout the27 weeks (p<0.05; Fig 1, left). The arm musclecircumference increased consistently among thestudy subjects; at 21 weeks, the increase was signif¬icantly greater in the study group compared with thecontrol group (p<0.05; Fig 1, center). Between-group differences in thigh circumference were de¬tectable at 3 weeks and increased progressivelyduring the study (p<0.05; Fig 1, right).Weight increased in 9 out of 10 subjects who

received anabolic steroids (mean, +1.8±0.5 kg;p<0.05), whereas the control group lost weight(mean, .0.4±0.2 kg) after 6 months. At baseline,

1.l.I.r3 6 9 12 15 18 21 24 27

weeks

i.i.i.i.i.i.i.i.r0 3 6 9 12 15 18 21 24 27

weeks

r.l.m.r3 6 9 12 15 18 21 24 27

weeks

anabolic steroid- control

Figure 1. Changes in anthropometric measurements in study subjects who received anabolic steroids(squares) and control subjects (circles). Left: percentage change in BMI. The study group's changes inBMI were significantly greater than the control group's throughout most of the study. Center:percentage change in arm muscle circumference (AMC). At 21 weeks, AMC had increased significantlymore in the study group than in the control group. Right: percentage change in thigh circumference.Significant between-group differences were detectable at 3 weeks and increased steadily throughoutthe study. *=p<0.05 (study group vs control group). #=p<0.05 (vs baseline).

22 Clinical Investigations 1998 by the American College of Chest Physicians



lean body mass as measured by DEXA was similar inboth groups. In subjects who received anabolicsteroids, lean body mass increased significantly at 9weeks compared with baseline (p<0.05; Fig 2, left),whereas control subjects showed no increase. Theincrease in the study group was sustained at 18weeks. There were no statistically significant changesin fat mass over time or differences between groups(Fig 2, right).

All subjects reported compliance with the trainingregimen. Both groups demonstrated increased respi¬ratory muscle strength at 27 weeks (20.0±11.0% inthe control group, 41.0±9.4% in the study group),although the increases were not significant; between-group differences were also not significant (Fig 3,left). There were no changes in PEmax (Fig 3, right).Changes in functional exercise capacity (6 MW)

and Vo2max were not significant in either group(Table 2).There were no significant differences in biochem¬

ical measures (electrolytes, glucose, calcium, phos¬phorus, magnesium), total protein, albumin, bloodcell count, prostatic acid phosphatase, or prostatesize within groups, between groups, or across time.Baseline levels of prostatic acid phosphatase were

2.7 IU/L and 2.5 IU/L in the control and studygroups, respectively, compared with 2.3 IU/L (con¬trol group) and 2.2 IU/L (study group) after 27weeks. The baseline prostate size was 25.8 and 28.0cm3 in the control and study groups, respectively,compared with 24.2 and 29.4 cm3 after 27 weeks.Levels of LH and testosterone were similar in both

groups at baseline but showed significant decreasesin those receiving anabolic steroids (Table 3). Thebetween-group differences for LH were evident at 9weeks and through 27 weeks. Testosterone levelswere significantly lower in the study group comparedwith the control group at 9 and 18 weeks. The resultsof all other screening tests for side effects of anabolicsteroids did not change.

Discussion

We undertook this randomized controlled trial inorder to evaluate the potential benefits of anabolicsteroids in malnourished individuals with COPDwhose BMI was less than 20 kg/m2 and whose PImaxwas below 60% of the predicted value. Such individ¬uals have been noted to have a reduced body fatcontent, skinfold thickness, and arm circumfer¬ence.16 At the end of the 6-month study, the controland treatment groups' weights differed, with subjectswho received anabolic steroids weighing an averageof 2 kg more than control subjects. This weight gainwas associated with significant increases in arm

muscle and thigh circumference and in lean bodymass as measured by DEXA.The improved nutritional status that we observed

was confined to those who received anabolic ste¬roids. Although the absolute weight gain amongthose receiving anabolic steroids in the study bySchols et al14 was not influenced by the nutritionalsupplement, the fat-free mass was significantly

_ 44-|

</> 42</>C3

OmcCO0

40

38 H

36

9 18 27

weeks

11 -j

10 H

g 9-|if)

8 8s15 7LL.

6

5

B

9 18

weeks

27

control anabolic steroid

Figure 2. Changes in lean body mass (left) and percent fat mass (right), as measured by DEXA, in

study subjects who received anabolic steroids (squares) and control subjects (circles). Left: at weeks 9and 18, the study group experienced a significant increase in lean body mass compared with baseline;no significant change was noted in control subjects. Right: no significant differences were notedbetween groups or over time. #=p<0.05 (vs baseline).




i.i.i.i.i.i.i.r3 6 9 12 15 18 21 24 27

weeks

~i i.i.i.r3 6 9 12 15 18 21 24 27

weeks

-.. control anabolic steroid

Figure 3. Changes in PImax and PEmax in study subjects who received anabolic steroids (squares) andcontrol subjects (circles). Left: both groups experienced an improvement in PImax (20.0% in thecontrol group, 41.0% in the study group), but the differences between the groups were not statisticallysignificant. Right: there were no significant changes in PEmax over time or differences between groups.

greater in those receiving both steroids and nutri¬tional supplements. Their placebo group lost 0.4 kg,as did our control subjects. The increase in lean bodymass that we observed without a nutritional supple¬ment (2.5 kg at 9 weeks and 1.9 kg at 27 weeks) was

similar in magnitude to that reported by Schols etal14 (1.4 kg at 8 weeks in nondepleted subjects and1.9 kg in depleted subjects), despite the use ofdifferent measurement techniques; Schols et al14used bioelectrical resistance.26 In our study, leanbody mass did not change in control subjects, butincreased in treatment subjects. Although statisticalsignificance was not reached at 27 weeks, the trendfor the increase was still evident (Figure 2). Fat mass

did not change in either group.Although Schols et al14 also measured body com¬

position and respiratory muscle strength in subjectswith COPD, our study differed in several ways. First,because we wanted to separate the influence of theanabolic steroid from that of nutritional supplemen¬tation, we did not modify subjects' nutritional intake.Second, we included IMT, which was not part of thestudy by Schols et al.14 Third, we chose to study an

oral anabolic steroid rather than a parenterally ad¬ministered steroid and administered it for 27 weeksin order to approximate an outpatient clinical ap¬proach to those with COPD; Schols et al14 gavesubjects a parenteral steroid for 8 weeks. Fourth, wewere concerned about side effects and performeddetailed monitoring of biochemical, hormonal, andhematologic measures, as well as both clinical andultrasound assessment of prostatic function.Although our subjects did undergo cycle training,

this training was not associated with increases inmeasurements of maximal or functional exercisecapacity. We selected malnourished, severely im¬paired individuals with COPD who had high targetexercise levels. Whereas a less impaired cohort mayhave improved more than our study subjects, theliterature suggests that improvements in exercisetolerance can be achieved among severely impairedindividuals.27 In their well-designed study, Schols etal14 succeeded in obtaining reliable measures offunctional exercise (12-min walk distances) in only62% of nutritionally depleted individuals. These

Table 2.Distance Walked in 6 Min and Vo2max in Control and Study Groups*Control Study

Baseline Week 9 Week 18 Week 27 Baseline Week 9 Week 18 Week 27

Six-min walk, mVo2max, % pred

540 (24)54.6 (6)

545 (29)57.5 (7)

561 (35)57.8 (5)

573(26)64.2 (8)

523 (19)56.8 (3)

540 (23)54.2 (7)

516 (27)55.0 (6)

510 (33)51.8 (6)

*Data presented as mean (SEM). % pred=percentage of predicted value.

24 Clinical Investigations



Table 3.LH and Testosterone Levels in Control and Study Groups*Baseline Week 9 Week 18 Week 27

LH, IU/LControl groupStudy group

Testosterone, ng/dLControl groupStudy group

5.7(1.7)3.3 (0.6)

496(117)415(34)

7.2 (2.3)0.66ft (0.2)

452 (43)157n (28)

7.1(1.8)1.8* (0.7)

463 (31)135n (14)

7.4 (2.0)2.1t(0.8)

402 (89)220f(61)

*Data presented as mean (SEM).fp<0.05 compared with baseline.+p<0.05 compared with control group.

authors did not identify any increase in 12-min walkdistances in their subjects.We observed clear trends in the measures of

respiratory muscle strength (increases of 20.0% and41.0% in the control and treatment groups, respec¬tively). However, the differences between the two

groups did not reach statistical significance. In theSchols et al14 study, nutritionally depleted individu¬als who received both anabolic steroids and nutri¬tional supplementation achieved a significant in¬crease in PImax at 8 weeks. Conceivably, a largersample size might have allowed us to detect a

statistically significant change. Alternatively, the sub¬jects in our study may have been too impaired to

experience a significant response to the trainingregimen. Another factor contributing to the lack ofchange in respiratory muscle function may have beenthe absence of supervision during IMT sessions. Thisis consistent with rehabilitation literature suggestingthat unsupervised training interventions are lesseffective than supervised interventions.28 Finally, therole of IMT in this population is questionable; even

among well-nourished individuals with COPD whounderwent training at highly controlled and super¬vised centers, the evidence of improvement in dys¬pnea or exercise capacity is equivocal.29

Malnutrition impairs skeletal muscle functionamong healthy individuals and those with respiratoryconditions. By affecting both ventilatory6'30'31 andperipheral muscles,32 malnutrition increases impair¬ment and likely adds to the disability of individualswith COPD. Malnourished subjects have beenshown in at least one report33 to have worse scores

for the impact and activity domains of a specificrespiratory quality-of-life questionnaire. Reductionsin muscle mass, especially in the lower limbs, are

common in elderly men,3435 this has been linked to

deconditioning as well as decreased production ofgrowth hormone and testosterone levels.3637 Insome men, the levels of testosterone, dehydroepi-androsterone, and dehydroepiandrosterone sulphatedecrease slowly, but in others, these hormones re¬

main within the normal range.38 In a study of 36

individuals with COPD, Roth et al39 noted that inthose who had experienced a weight loss of more

than 4.5 kg in the preceding 6 months or those inwhom weight was below 90% of the predicted value,the incidence of hypogonadism was higher than inthose with normal weights. Although both an animalstudy40 and an uncontrolled clinical study41 havesuggested that growth hormone may be of benefit,growth hormone is expensive and has side effects; in

elderly men, growth hormone was no better than a

placebo when evaluated in conjunction with physicaltraining.42 When administered to 12 subjects withCOPD, growth hormone plus exercise training re¬

sulted in greater increases in lean body mass andmuscle cross-sectional area than either placebo plustraining (12 subjects) or placebo alone (five sub¬jects), with no measurable between-group differ¬ences in exercise tolerance.43A wide range of responses to anabolic steroids has

been reported. Anabolic steroids have been claimedto increase muscle mass and performance amongathletes by inducing an anabolic effect on proteinsvia androgenic receptors as well as by inhibitingprotein catabolism via glucocorticoid receptors.11Testosterone stimulates muscle growth via its effectson somatomedin,8 influences actin and myosin toincrease strength,44-46 and might even act centrally tostimulate athletes to strive for higher training inten¬sities.94748 Unfortunately, accurate reports on theeffects of anabolic steroids have been difficult to

obtain; there have been wide variations in dosagesand methods of administration, as well as a relativepaucity of well-designed outcome studies. In a well-designed study by Bhasin et al,13 supraphysiologicdoses of testosterone were administered to healthymale volunteers, some of whom also received super¬vised weight training three times per week. Theauthors reported significant improvements in musclesize and strength between placebo and testosteronein nonexercising groups and greater increases infat-free mass, muscle size, and strength among thosereceiving testosterone in the exercising groups.




There were no side effects in mood or behaviorattributable to testosterone.13The effects of anabolic steroids on the athlete and

athletic performance remain controversial. Thereappears to be a consensus, however, regarding theeffects of anabolic steroids on aerobic metabolism:no beneficial effect of anabolic steroids has ever

been shown on aerobic metabolism or an individual'sVo2max.10The clinical applications of anabolic steroids have

been acknowledged for some time. They have beenadministered as adjuvants in the management ofprotein deficiency states, after major surgery or

severe trauma, for malabsorption during radiother¬apy, and in conjunction with cytotoxic chemothera¬py.49 Anabolic steroids have also been included withparenteral nutrition and have been shown to have a

markedly beneficial effect.50 The response to ana¬

bolic steroids has been most favorable among thosein negative nitrogen balance. Undernourished el¬derly people respond to steroids with marked nitro¬

gen retention and significant weight gain.51

Justification of MethodsTestosterone cannot be effectively administered

by mouth, as it is rapidly absorbed into the portalblood stream for degradation by the liver. Thus, onlya small amount reaches the systemic circulation.When administered parenterally, effective levels are

not sustained in the plasma because anabolic steroidsare promptly degraded.11 We chose to use stanozolol(a synthetic substance derived from testosterone),which can be orally administered. Synthetic deriva¬tives have the added advantage of having more

anabolic and less androgenic effects than naturaltestosterone. The dosage we selected, 12 mg per day,is twice the replacement dosage10 and is the dosageconventionally used by athletes.11 We used one doseof IM testosterone at the start of the study as an

"attack" dose, in keeping with the approach pre¬ferred by athletes. Generally, athletes use either a

pyramidal administration schedule, starting with lowdaily dosage and building to higher dosages, or theyuse a "stacking" schedule in which several differentpreparations are taken simultaneously (oral and par¬enteral).38-47During the administration of stanozolol, testoster¬

one levels decreased significantly at weeks 9, 18, and27. At week 27, the differences between groups werenot statistically significant even though the levels oftestosterone in the anabolic steroid group were

comparable to prepubertal levels.52We used DEXA to measure body composition.

This method has been shown to be accurate to within1.5% for measurements of total body mass as well as

fat and lean mass percentages.53 The advantage ofDEXA for composition studies is that it requires only10 to 20 min to complete, involves minimal exposureto radiation, and gives regional values as well as totalbody values. The reproducibility is such that serialmeasurements are routinely used in estimates ofcalcium balance and are accurate to within 0.8%.53We used Lunar DPX, which is a precise and accuratetool for the assessment of whole body composition.54Since there is no method available to measure bodycell mass in clinical practice, it is generally acknowl¬edged that in absence of fluid shifts, the fat-free massprovides an acceptable estimate.55 In our study, theincrease in lean body weight cannot be equatedunequivocally to an increase in muscle or tissue mass

because fluid retention could not be absolutely ruledout. However, regular clinical evaluation by the samephysician did not reveal clinical evidence of fluidretention nor any change in BP. In addition, DEXAscanning was standardized to be performed at thesame time of the day (late morning, before lunch)and by the same technician.

In our study, the dietary intake of our subjectsremained open, without any attempt at standardiza¬tion or supplementation. Supplementation has beenshown to be useful when provided to patients withCOPD in conjunction with anabolic steroids.14 Manyof our study subjects spontaneously reported an

increase in their appetite, consistent with reports on

the influence of anabolic steroids on appetite.38However, even in the absence of supplementation,BMI and muscle circumference increased amongthose who received anabolic steroids.Our relatively small sample size may have influ¬

enced the power of our measurements. For example,there appeared to be a clinical effect of anabolicsteroids on PImax but this did not reach statisticalsignificance, possibly because of the lack of power ina small sample. Further studies on the influence ofanabolic steroids should examine a larger sample andshould also evaluate their influence on health-relatedquality of life.

In summary, anabolic steroids administered to

severely impaired, malnourished men with COPDwere associated with a greater increase in weight,fat-free mass, and arm and thigh muscle circumfer¬ence than was placebo. There was a trend for an

increase in inspiratory muscle strength in bothgroups. These changes occurred in the absence ofclinical or biochemical side effects.

ACKNOWLEDGMENTS: The authors acknowledge the assis¬tance of Drs. Agnaldo P. Cedegno (Urology), N. Ferreira Novoand Y. Juliano (Statistics), J.G.H. Vieira (Endocrinology), JoseLazaro de Andrade (Echocardiography), Celso Guerra (Haema-tology), Sergio Ayzen (Radiology), and Braulio Luna Filho (Car¬diology).




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DOI 10.1378/chest.114.1.19 1998;114; 19-28Chest

Goldstein, Noe Zamel, Dina Brooks and Jose R. JardimIvone Martins Ferreira, Ieda T. Verreschi, Luiz E. Nery, Roger S.and Respiratory Muscles in Undernourished COPD Patients

The Influence of 6 Months of Oral Anabolic Steroids on Body Mass

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